AU2006310591B2

AU2006310591B2 - Novel process for the preparation of acid chlorides

Info

Publication number: AU2006310591B2
Application number: AU2006310591A
Authority: AU
Inventors: Ursula Hoffmann; Goesta Rimmler
Original assignee: F Hoffmann La Roche AG
Current assignee: F Hoffmann La Roche AG
Priority date: 2005-10-31
Filing date: 2006-10-19
Publication date: 2012-03-15
Anticipated expiration: 2026-10-19
Also published as: ATE537136T1; AU2006310591A1; CN101300219A; TWI313677B; ES2377570T3; JP5148500B2; BRPI0618267B1; US7435849B2; CA2626102A1; US20090036703A1; EP1945601B1; IL190551A; CA2626102C; WO2007051714A1; JP2009513686A; BRPI0618267A2; US20070100154A1; KR20080061385A; EP1945601A1; KR100980522B1

Abstract

A process for the preparation of acid halides of formula (I) which are useful as intermediates in the preparation of i.a. pharmaceutically active compounds.

Description

-1 NOVEL PROCESS FOR THE PREPARATION OF ACID CHLORIDES The present invention is directed to a process for the preparation of acid halides which are useful as intermediates in the preparation of i.a. pharmaceutically active compounds. 5 Disclosed herein is a process for the preparation of a compound of formula I CI wherein t o R' is hydrogen, Ci-Csalkyl or C 2

-C

8 alkenyl which are unsubstituted or substituted by one or more substituents selected from CI-Csalkoxy and C 3 -Cacycloalkyl; and

R

2 and R 3 together are C 3 -alkylenyl or C 3 -alkenylenyl; comprising reacting a compound of formula II 15 OH wherein R', R 2 and R 3 have the above meanings; with thionylchloride in the presence of a tri-Ci-Csalkylamine. In one aspect the present invention provides a process for the preparation of a compound of formula I 20 R' (1) CI wherein R' is hydrogen, Ci-Csalkyl or C 2

-C

8 alkenyl which are unsubstituted or substituted by one or more substituents selected from Ci-Csalkoxy and C3-Cgcycloalkyl; and 25 R 2 and R 3 are combined with the carbon atom to which they are attached to form

C

3

-C

7 -cycloalkyl or C 5 -Cscycloalkenyl; comprising reacting a compound of formula II

R

2 R* OH 30 wherein R', R 2 and R 3 have the above meanings; -2 with thionylchloride in the presence of a tri-Ci-C 5 alkylamine. Specifically, a first aspect of the present invention provides a process for the preparation of a compound of formula I ci 5 C1 wherein R' is hydrogen, Ci-Csalkyl or C 2

-C

8 alkenyl which are unsubstituted or substituted by one or more substituents selected from Ci-Csalkoxy and C 3

-C

8 cycloalkyl; and la R 2 and R 3 are combined with the carbon atom to which they are attached to form

C

3

-C

7 -cycloalkyl or C5-Cgcycloalkenyl; comprising reacting a compound of formula II OH I5 1 2 3 wherein R , R and R 3 have the above meanings; with thionylchloride in the presence of tributylamine. The compounds of formula I may be used as intermediates in the synthesis of valuable pharmaceutical compounds, e.g. those as described in e.g. EP 1,020,439. 20 Accordingly, in another embodiment the present invention provides a process comprising the synthetic steps represented in the following scheme: R' R30 RRf' R 2 HN SS NH HS NH ,

-R

4 0(O)S NH 0 25 wherein R', R 2 and R 3 are as defined above and R 4 is Ci-Csalkyl. In particular, the process comprises reacting a compound of formula I with bis(2-aminophenyl)disulfide to acylate the amino groups of the (2-aminophenyl)disulfide, reducing the amino-acylated disulfide product with a reducing agent such as triphenylphosphine, zinc or sodium - 2a borohydride to yield the thiol product, and acylating the thiol group in the thiol product with R 4 C(O)Cl. The additional steps may be performed, e.g., according to the procedures described in Shinkai et al., J. Med. Chem. 43:3566-3572 (2000). 5 Examples for Ci-Csalkyl include methyl, ethyl, straight and branched propyl, butyl, pentyl, hexyl, e.g. CH 2

CH(CH

2

CH

3

)

2 , heptyl and octyl. For R', Ci-Csalkyl is preferably

CH

2

CH(CH

2

CH

3

)

2 . For R 4 , CI-CsaIkyl is preferably isopropyl. Examples for C 2 -Csalkenyl include unsaturated carbon chains containing one or more double bonds at any possible position, e.g. vinyl, allyl, butenyl, pentenyl, hexenyl, 10 heptenyl and octenyl.

WO 2007/051714 PCT/EP2006/067570 -3 Examples for C 3

-C

7 cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Preferred is e.g. cyclohexyl. Examples for C 5 -Cscycloalkenyl include cyclo pentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclopentadienyl, cyclohexadienyl, cycloheptadienyl and cyclooctadienyl. Preferred are cyclopentenyl, cyclohexenyl and 5 cycloheptenyl. The term "tri-Ci-C 5 alkylamine" denotes a compound of formula R 4 N(R)R wherein R 4 ,

R

5 and R 6 independently are a CI-Csalkyl, and includes triethylamine, tributylamine, di ethyl-methylamine, dimethyl-ethylamine and methylethylbutylamine. The process may take place at a temperature in the range from 20 to 60C, e.g. in a range 10 from 40 to 55C. The process may be performed without a solvent or in the presence of a solvent, e.g. in the presence of an aromatic or chlorinated solvent, e.g. in the presence of methylene chloride, chloroform, toluene or benzene, e.g. in the presence of toluene. The acylating steps of the present invention are preferably conducted in the presence of a 15 base. Preferred bases include organic bases with pyridine being a preferred organic base. The amout of thionylchloride in relation to the compound of formula I in the reaction mixture may be in the range from 1.0 to 2.0 equivalents of thionylchloride, e.g. from 1.0 to 1.2 equivalents, e.g. 1.2 equivalents. The amount of the tri-C1-C 5 alkylamine in relation to the amount of the compound of 20 formula I may be at a ratio of from 5 mol% to 0.1 mol%, e.g. from 0.3 mol% to 0.5 mol%, e.g. 0.3 mol%. In another aspect the present invention provides a process for the preparation of a com pound of formula I as above, comprising reacting a compound of formula II as above in the presence of a tri-C 1

-C

5 alkylamine by continuously adding thionylchloride. 25 The term "continuously adding" denotes the addition of thionylchloride to a solution of compound I and optionally a solvent during a period of time from 10 minutes to 5 hours, depending on the batch size. The solution of compound I and optionally a solvent is heated to the desired temperature prior to the addition of thionylchloride. This method is different from the batch mode where all components are mixed at RT and the mixture is 30 heated to the desired temperature.

WO 2007/051714 PCT/EP2006/067570 -4 In one embodiment the present invention provides a process for the preparation of a com pound of formula I wherein R is -CH 2

CH(CH

2

CH

3

)

2 . In another embodiment the present invention provides a process for the preparation of a compound of formula I wherein the tri-C1-C 5 alkylamine is triethylamine or tributylamine. In still another embodiment the pre 5 sent invention provides a process for the preparation of a compound of formula I wherein the tri-C1-C 5 alkylamine is tributylamine. The compounds of formula II are commercially available or can be prepared by procedures known to the skilled person. In general, the nomenclature used in this Application is based on AUTONOMm v.4.0, a 10 Beilstein Institute computerized system for the generation of IUPAC systematic nomen clature. Chemical structures shown herein were prepared using ISIS®version 2.2. Any open valency appearing on a carbon, oxygen or nitrogen atom in the structures herein indicates the presence of a hydrogen atom. Example 1: Preparation of 1-(2-Ethyl-butyl)-cyclohexanecarbonyl chloride in the 15 absence of a catalyst A mixture of 103.0 mmol 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid and 38.9 mmol cyclohexanecarboxylic acid was warmed to 50'C. 12.4 mL (170.3 mmol =1.2 Eq. relative to the sum of both acids) of thionyl chloride was added during 16 minutes at a temperature of 44-50C (reaction is endothermic) and the reaction mixture was kept at 52-53'C. After 1 hr 20 the reaction was incomplete (5.2% 1-(2-etbyl-butyl)-cyclohexanecarboxylic acid and 13.8% 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid anhydride), after 6 hrs still incomplete (1.9% 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid and 2.8% 1-(2-ethyl-butyl)-cyclo hexanecarboxylic acid anhydride). After addition of another 4.0 mL (55 mmol) thionyl chloride and 3 hr at 52-53'C the reaction was almost complete (0.18% 1-(2-ethyl-butyl) 25 cyclohexanecarboxylic acid and 0.47% 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid an hydride). After removing volatile components in vacuo (60'C bath, 3.3-3.7 mbar followed by 120'C bath, 9.3-9.6 mbar) 20.21 g of residue was obtained (assay 96.6% 1-(2-ethyl butyl)-cyclohexanecarbonyl chloride, yield 82.1%). Example 2: Preparation of 1-(2-Ethyl-butyl)-cyclohexanecarbonyl chloride in the 30 presence of 0.02 Eq. triethylamine WO 2007/051714 PCT/EP2006/067570 -5 A mixture of 103.0 mmol 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid, 38.9 mmol cyclo hexanecarboxylic acid and 396 VL triethylamine (2.84 mmol=0.02 eq. relative to the sum of both acids) was warmed to 50'C. 12.4 mL (170.3 mmol =1.2 Eq. relative to the sum of both acids) of thionyl chloride was added during 18 minutes at a temperature of 40-54 0 C 5 (reaction is endothermic, vigorous gas evolution) and the reaction mixture was kept at 54 55'C. After 1 hr reaction was complete (0.03% 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid and no 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid anhydride). After removing volatile components in vacuo (60'C bath, 3.5-4.3 mbar followed by 120'C bath, 10-11 mbar) 25.44 g of residue was obtained (assay 92.9% 1-(2-ethyl-butyl)-cyclohexanecarbonyl 10 chloride, yield 99.4%) Example 3: Preparation of 1-(2-Ethyl-butyl)-cyclohexanecarbonyl chloride in the presence of 0.005 Eq. triethylamine A mixture of 103.0 mmol 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid, 38.9 mmol cyclo hexanecarboxylic acid and 100 VLtriethylamine (0.72 mmol=0.005 eq. relative to the sum 15 of both acids) was warmed to 50C. 12.4 mL (170.3 mmol =1.2 Eq. relative to the sum of both acids) of thionyl chloride was added during 22 minutes at a temperature of 41-51C (reaction is endothermic, vigorous gas evolution) and the reaction mixture was kept at 54 55'C. After 10 minutes the reaction was almost complete (0.13% 1-(2-ethyl-butyl)-cyclo hexanecarboxylic acid and 0.13% 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid anhydride). 20 After 1.5 hr the reaction was complete (0.04% 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid and no 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid anhydride). After removing volatile components in vacuo (60'C bath, 3.5-4.3 mbar followed by 120'C bath, 10-11 mbar) 26.19 g of residue was obtained (assay 92.9% 1-(2-ethyl-butyl)-cyclohexanecarbonyl chloride, yield 100%). 25 Example 4: Preparation of 1-(2-Ethyl-butyl)-cyclohexanecarbonyl chloride in the presence of 0.005 Eq. tributylamine A mixture of 103.0 mmol 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid, 38.9 mmol cyclo hexanecarboxylic acid and 173 pLtributylamine (0.71 mmol=0.005 eq. relative to the sum of both acids) was warmed to 50C. 12.4 mL (170.3 mmol =1.2 Eq. relative to the sum of 30 both acids) of thionyl chloride was added during 16 minutes at a temperature of 44-51'C (reaction is endothermic, vigorous gas evolution) and the reaction mixture was kept at 53 55 0 C. After 15 minutes the reaction was complete (0.08% 1-(2-ethyl-butyl)-cyclohexane carboxylic acid and no 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid anhydride). After re- WO 2007/051714 PCT/EP2006/067570 -6 moving volatile components in vacuo (60'C bath, 2.7-1.9 mbar followed by 120'C bath, 8.8-13 mbar) 24.86 g of the residue was obtained (assay 95.8% 1-(2-ethyl-butyl)-cyclo hexanecarbonyl chloride, yield 100%).

Claims

1. A process for the preparation of a compound of formula I C1 5 wherein R' is hydrogen, Ci-C 8 alkyl or C 2 -C 8 alkenyl which are unsubstituted or substituted by one or more substituents selected from Ci-Csalkoxy and C 3 -C 8 cycloalkyl; and R2 and R 3 are combined with the carbon atom to which they are attached to form io C 3 -C 7 -cycloalkyl or C5-C 8 cycloalkenyl; comprising reacting a compound of formula II OH 1 2 3 is wherein R , R and R 3 have the above meanings; with thionylchloride in the presence of tributylamine.

2. The process according to claim I additionally comprising the step of acylating a compound of the formula III HN S~S NH 20 with a compound of formula I to yield a compound of formula IV H~b SS6 NH(TV) HN S~SNH 25 1 2 3 wherein R , R and R are as defined in claim 1. -8

3. The process according to claim 2 additionally comprising the step of reducing the compound of formula IV with a reducing agent to yield a compound of formula V R3 2 HS NH V) 0 5 1 2 3 wherein R , R and R are as defined in claim 1.

4. The process according to claim 3 additionally comprising the step of acylating the compound of formula V with R 4 C(O)Cl to yield a compound of formula VI R R R'C(O)S NH (VI) 10 wherein R', R 2 and R3 are as defined in claim l and R 4 is CI-Csalkyl.

5. The process according to claim 4 wherein R 4 is isopropyl.

6. The process according to any one of claims I to 5 wherein the thionyl 15 chloride is present in the range from 1.0 to 2.0 equivalents of thionylchloride in relation to the compound of formula I.

7. The process according to any one of claims I to 6 wherein the amount of the tributylamine in relation to the amount of the compound of formula I is at a ratio of from 5 mol% to 0.1 mol%. 20

8. The process according to any one of claims I to 7 wherein thionylchloride is continuously added.

9. The process according to any one of claims 1 to 8 wherein in formula I R 2 and R 3 are combined with the carbon atom to which they are attached to form C 3 C 7 cycloalkyl. 25

10. The process according to any one of claims I to 8 wherein in formula I R1 is CH 2 CH(CH 2 CH 3 ) 2 and R 2 and R 3 are combined with the carbon atom to which they are attached to form cyclohexyl.

11. The process according to claims 2 to 4 wherein the acylating steps are performed in the presence of a base. -9

12. The process according to claim 11 wherein the base is an organic base.

13. The process according to claim 12 wherein the organic base is pyridine. Dated 7 February, 2012 F. Hoffmann-La Roche AG 5 Patent Attorneys for the Applicant/Nominated Person SPRUSON & FERGUSON